The human body has a self-healing or defensive system for healing and prevention of loss of blood at wound sites, which is achieved by modulation and balancing among clotting of platelets and plasma, degradation of fibrin, and inhibition of coagulation. When these proper control and balance are disturbed by various factors, abnormal platelet aggregation occurs and that leads to thrombotic diseases.
Thrombosis refers to a condition wherein the blood circulation system is disturbed by a blood clot in the blood vessel, or in the worst case, the flow of blood is blocked. Thrombosis may cause atherothrombosis, phlebothrombosis, hepatic portal vein thrombosis, pulmonary thromboembolism, chronic limb ischemia, varicose veins, deep vein thrombosis diseases, angina pectoris, cerebral infarction, cerebral hemorrhage, and the like, and it may also contribute to infection, vascular injury, postoperative complications, coagulative diseases, and the like. Such thrombosis can be generated by interaction among abnormal blood vessel walls, hemodynamic forces, coagulation proteins in the plasma, and platelets. Platelets are activated by various agonists such as adenosine diphosphate, thromboxane A2, and thrombin, and the activated platelet glycoproteins such as IIb/IIIa are combined with aggregation proteins in the blood (fibrinogen, von Willebrand factor, etc.) to cause an aggregation reaction.
Recently, it has been known that platelets are abnormally activated not only by chemical agonists but also by physical stimulation, resulting in thrombosis. Among the physical stimuli, shear stress is the most influential factor in platelet activation. Shear stress refers to the force of the bloodstream on the cells within the blood vessels, such as platelets, red blood cells and endothelial cells. An abnormal change in shear stress is the major cause of pathologic arterial thromboli development in vivo, which is caused by artery dissection due to percutaneous coronary intervention such as stent, atherectomy, and balloon angioplasty; vascular spasm; or diseases such as hypertension and atherosclerosis.
When the shear stress increases abnormally, platelets are activated, and the glycoproteins IIb/IIIa of the activated platelets directly bind to von Willebrand factor, resulting in aggregation. These phenomena accelerate the signaling pathway in platelets, increase intracellular calcium concentration, and induce the release of various activating factors from granules, thereby promoting platelet aggregation and producing thrombosis (Nesbitt et al., Nature Medicine 15, 665-673 (2009)).
The currently used agents for the prevention and treatment of thrombotic diseases include antiplatelet agents that antagonize chemical agonists (e.g., aspirin, clopidogrel, etc.), anticoagulants (e.g., heparin, warfarin, etc.), thrombolytic agents for treating preformed thrombli (e.g., tissue plasminogen activator, etc.), and so on. Aspirin is known to cause side effects such as gastrointestinal bleeding and peptic ulcer, although it is fairly effective. Most of the other anticoagulants cannot be orally administered and exhibit various side effects after prolonged administration such as hemorrhage, hemolysis, immune reaction, fever and allergy, because of their low selectivity for thrombosis. In addition to these side effects and ineffectiveness, there is another problem of prohibitively expensive prices of some commercially available therapeutic agents.
For the above reasons, there is a need to develop an antiplatelet agent that selectively affects shear stress-induced platelet aggregation and has few side effects (Kiefer and Becker, Circulation, 2009, 120:2488-2495/Gilbert et al., Circulation, 2007, 116:2678-2686).